Relationship Between White Matter Lesions and Gray Matter Atrophy in Multiple Sclerosis

Background and Objectives There is currently no consensus about the extent of gray matter (GM) atrophy that can be attributed to secondary changes after white matter (WM) lesions or the temporal and spatial relationships between the 2 phenomena. Elucidating this interplay will broaden the understanding of the combined inflammatory and neurodegenerative pathophysiology of multiple sclerosis (MS), and separating atrophic changes due to primary and secondary neurodegenerative mechanisms will then be pivotal to properly evaluate treatment effects, especially if these treatments target the different processes individually. To untangle these complex pathologic mechanisms, this systematic review provides an essential first step: an objective and comprehensive overview of the existing in vivo knowledge of the relationship between brain WM lesions and GM atrophy in patients diagnosed with MS. The overall aim was to clarify the extent to which WM lesions are associated with both global and regional GM atrophy and how this may differ in the different disease subtypes. Methods We searched MEDLINE (through PubMed) and Embase for reports containing direct associations between brain GM and WM lesion measures obtained by conventional MRI sequences in patients with clinically isolated syndrome and MS. No restriction was applied for publication date. The quality and risk of bias in included studies were evaluated with the Quality Assessment Tool for observational cohort and cross-sectional studies (NIH, Bethesda, MA). Qualitative and descriptive analyses were performed. Results A total of 90 articles were included. WM lesion volumes were related mostly to global, cortical and deep GM volumes, and those significant associations were almost without exception negative, indicating that higher WM lesion volumes were associated with lower GM volumes or lower cortical thicknesses. The most consistent relationship between WM lesions and GM atrophy was seen in early (relapsing) disease and less so in progressive MS. Discussion The findings suggest that GM neurodegeneration is mostly secondary to damage in the WM during early disease stages while becoming more detached and dominated by other, possibly primary neurodegenerative disease mechanisms in progressive MS.

Gray matter (GM) atrophy occurs in patients with multiple sclerosis (MS) e1 already in early disease stages. e2,1 Reflecting axonal loss and irreversible neuronal damage, 2 GM atrophy can be measured noninvasively in vivo from standard MRI. It is considered a marker of neurodegeneration that could help bridge the current gap between measures of clinical disability and traditional inflammatory MRI markers. 3 Recent work has found that MS pathology affects both GM and white matter (WM) structures throughout the CNS. Therefore, it is unlikely that disability progression and worsening of higher functions such as cognition can be strongly predicted by a single MRI marker. 4 Nevertheless, brain GM atrophy is associated with several clinical outcomes: GM volumes are lower in people with MS than in healthy controls, 5 may predict conversion from clinically isolated syndrome (CIS) to MS, 6,7 and relate to disability progression. 8 Moreover, GM atrophy relates strongly with cognitive dysfunction [9][10][11][12][13] and more so than WM lesion volume (LV). 14 WM lesions have been the principal imaging marker of disease activity and progression in MS and are incorporated into diagnostic criteria 15 and treatment goals, 16 as well as outcome measures in research trials. These focal areas of demyelination, consisting of inflammation and variable gliosis, 17 can be visualized as hyperintense or hypointense lesions in T2-and T1weighted MRIs, respectively. 3 If and how WM lesions and GM atrophy are temporally, spatially, and causally related are insufficiently clear. Elucidating this interplay will not only broaden understanding of the combined inflammatory and neurodegenerative pathophysiology of MS but also provide reliable biomarkers for research and therapeutic purposes. As treatment targets expand from inflammatory lesions to neurodegenerative processes, GM atrophy is a natural choice of outcome measure. Separating atrophic changes due to primary and secondary neurodegenerative mechanisms will then be crucial to properly evaluate treatment effects, especially if these treatments target the different processes individually. While some studies have addressed the relationship between WM lesions and GM atrophy directly, a larger body of literature reports measures of both. In this systematic review, we have therefore aimed to review this existing evidence in its entirety to establish how brain WM lesions and GM atrophy in MS are related.

Methods
This review was conducted and presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 18

Search Strategy
To select studies of relevance to this systematic review, the electronic databases Medline (through PubMed) and Embase were searched. The search strategies were developed in consultation with a medical librarian (M.A.E.M.). Thesaurus terms and free-text words, including synonyms and closely related words, were used for the following concepts: MS, GM atrophy, and WM lesions. No restrictions were applied for language (at this stage) or publication date, but conference abstracts were excluded. The search strategy is detailed in eAppendix 1, links.lww.com/WNL/B816. The last search was conducted on August 17, 2020.

Eligibility Criteria
Studies were included if they fulfilled all following criteria: (1) controlled trials or observational studies in English and published in a peer-reviewed journal; (2) trials or studies that involved patients diagnosed with CIS or MS; and (3) study abstract containing associations between brain GM and WM lesion measures obtained by conventional MRI sequences. To limit the scope of this review and the possible variability in pathologic substrates and disease mechanisms, we excluded studies of patients diagnosed with pediatric MS or with radiologically isolated syndrome.

Outcome Measures
The primary outcome measures of interest were direct associations made between brain WM lesion and GM atrophy measures, obtained by conventional MRI sequences, in patients diagnosed with CIS or MS.

Selection Process
After excluding duplicate publications, we screened the remaining abstracts on selection criteria by 2 independent raters (H.V., I.A.L.) using Rayyan software, 19 a web-based application designed for systematic reviews. 20 Conflicting selections were discussed until consensus.When eligibility could not be determined from the title and abstract alone, full texts of potentially relevant articles were consulted.

Data Extraction and Quality Assessment
Independent extraction and quality assessment of relevant data from each included article were conducted by at least 2 reviewers (I.A.L., M.M.W., R.M.M., H.V.), according to a customized checklist. The quality and risk of bias in included studies were further evaluated with the Quality Assessment Tool for observational cohort and cross-sectional studies (NIH, Bethesda, MA). A rating scale of yes = 1, no = 0, and not reported = 0 was applied for the 14 questions of the checklist, and the final study quality was rated, in consensus between the Glossary CGM = cortical GM; CIS = clinically isolated syndrome; DGM = deep GM; GM = gray matter; LV = lesion volume; MS = multiple sclerosis; PPMS = primary progressive MS; RRMS = relapsing-remitting MS; SPMS = secondary progressive MS; WM = white matter. raters (I.A.L. and H.V.), as good, fair, or poor on the basis of individual scores and the severity of the risk of bias.
To visually illustrate the main results for the different disease phenotypes, composite figures were prepared combining available, clear figures from key studies.

Results
Through the initial search, 3,750 records were identified. After the updated search and removal of duplicates, 2,260 citations were screened on title and abstract, resulting in 106 full-text articles considered, of which 90 articles met the inclusion criteria and were included in this review ( Figure 1). The 90 studies are listed in the eReferences (e1-e90, links.lww.com/ WNL/B816), and the study design in all included articles is described in Table 1. Last, the quality assessment rate for each study is reported in eTables 1-3.

Clinically Isolated Syndrome
Eight cross-sectional and 4 longitudinal studies investigated patients diagnosed with CIS. In the longitudinal studies, the follow-up period ranged from 2 to 5.5 years.
The association of lesions with global GM measures were reported in 5 studies, while cortical GM (CGM) and deep GM (DGM) measures were each considered in 7 studies. Four studies reported regional WM lesion measures.
Included studies are described in eTables 1-3, links.lww.com/ WNL/B816, and a more detailed discussion of results of each section is in eAppendix 2.
Global GM in CIS In 2 of 3 cross-sectional CIS studies, no significant association was found between global GM volume and either T2 e3 or T1 e4 LV. One study found a significant correlation between T2 LV and global GM volume (r = −0.56, p < 0.020). e5 The longitudinal relationship of global GM volume with global WM lesion measures was reported in 2 studies (follow-up time ranging from 2-3 years), both observing significant but different associations. In 1 study, change in global GM fraction correlated with WM LV changes (r values ranging from −0.3071 to −0.4280, p values from 0.0032 to 0.0426) but not with baseline lesion measures, e6 while the other study found associations with baseline lesion measures (p ≤ 0.004), but not with LV changes. e7

CGM in CIS
In cross-sectional CIS studies, lower CGM volume showed variable associations with global WM lesion measures. Two studies observed a significant relationship with the presence (t = 2.48, p = 0.020) e8 or volume (r = −0.49, p = 0.045) e5 of T2 lesions, while 3 studies did not. e2,e3,e8 Of 2 studies reporting regional WM lesion measures, 1 study found a significant association between regional cortical thickness and T2 LV (p ≤ 0.0466), e9 while the other did not. e8 Of the 2 available longitudinal studies, 1 study found no relations, e10 while the other found significant associations of cortical volume change over 48 months with baseline WM lesion measures (p ≤ 0.004) and the total cumulative number of new/enlarging T2 lesions (p = 0.036), while no associations were observed for LV changes. e7

DGM in CIS
In the 5 available cross-sectional studies in patients with CIS, all except 1 study e3 showed significant associations between global e2,e4 and regional e11,e12 WM LV and total e2 and regional DGM volumes e2,e4,e11,e12 (p values ranging from <0.0001-0.05). In contrast, no associations with DGM volumes were found for global T2 lesion number or the presence of gadolinium-enhancing lesions. e2 Of the regional DGM volumes investigated, the most consistent relationships were found for the thalamus and hippocampus. This pattern was true considering both global e2,e4 and regional WM LV. e11,e12 Longitudinally, 1 of the 3 available studies found that regional DGM atrophy was related to global baseline lesion measures (p ≤ 0.018), e7 but there was no relationship with changes in global e7,e10 or regional e11 LV (follow-up times between 2 and 5.5 years).
Relapsing-Remitting MS Overall, 37 cross-sectional and 14 longitudinal studies reported associations between WM lesion measures and GM atrophy in relapsing-remitting MS (RRMS). The follow-up period of the available longitudinal studies ranged from 1 to 5.5 years.
Seventeen publications reported the relationship with global GM, 29 on that with CGM, and 25 on that with DGM measures. Eleven studies considered regional WM lesion measures.
Included studies are described in eTables 1-3, links.lww.com/ WNL/B816, and a more detailed discussion of results of each section is given in eAppendix 2. Figure 2 illustrates the main results from this section.

Global GM in RRMS
The majority of available cross-sectional RRMS studies, i.e., 8 of 10 studies, observed significant associations between global GM volume and global WM lesion load. Eight studies observed a significant association between global GM volumes and T1 e13,e14 and T2 LV e13-e19 and abnormal WM e20 (p values ranging from <0.001-0.047). In contrast, 2 studies considering T2 LV e21,e22 and another 2 studies considering gadolinium-enhancing LV e13,e14 did not.
One cross-sectional study investigated the impact of regional LV on total GM volume and reported a significant correlation with regional T1 and T2 LV in 3 and 4 of 26 WM regions, respectively (r values ranging from −0.20 to −0.50, p < 0.001). e23 Of the 7 longitudinal studies available, 4 did not find an association between global GM atrophy progression and global WM lesion measures. When considering gadolinium-enhancing lesion measures obtained at baseline, 1 study found a significant association (p = 0.04), e24 while 3 others did not find that global GM atrophy progression related to the presence, e25,e26 number, e26 or volume e14 of gadolinium-enhancing lesions (follow-up time ranging from 1-4 years).
Three of 5 studies considering longitudinal WM lesion changes e14,e24,e27-e29 with a follow-up period between 1 and 4 years observed significant associations between longitudinal changes in T1 e27 and T2 e24,e27,e28 LV and GM atrophy progression (p values ranging from 0.0004-0.03).

Cross-sectional and longitudinal studies 8
Observational case-control 4 Observational cohort 2 Clinical trial 2 associations in areas in the frontal, temporal, cingulate, and insular cortex. A similar pattern of associations was seen for cortical thickness measures. e30,e35,e39 Five studies did not find significant relations for either cortical volume e21,e40-e42 or cortical thickness. e39 In 6 of the 8 cross-sectional studies e9,e23,e35,e43-e47 considering regional distribution of WM lesions, the results suggested an anatomic or structural relationship between lesion location and regional cortical volume e44,e45 and thickness. e9,e35,e46,e47 Considering global WM lesion measures, 3 of five e10,e27,e32,e48,e49 longitudinal studies found significant relationships between both baseline WM lesion measures e49 and on-study changes in WM LV e27,e48 or numbers e48 and cortical thinning (p = 0.040), e48 as well as regional (p < 0.01) e27 and total cortical volume loss (p values ranging from <0.0001-0.010) e49 (follow-up time ranging from 1-2 years).
Of the 2 studies assessing regional WM LV, 1 study observed visually that the increase in T2 LV spatially coincided with areas of cortical decrease, e50 while the other study did not. e51 While 2 cross-sectional studies did not find any associations between regional WM lesion and DGM measures, e23,e45 the majority of studies did. e43,e44,e46,e54

DGM in RRMS
All 4 publications that assessed longitudinal relations between total and regional DGM atrophy and global WM lesion measures observed significant associations. e10,e48,e49,e57 The associations were found for both baseline WM lesion measures (p < 0.0001 and 0.037) e49,e57 and on-study new/  The 1 study considering regional T1 and T2 LV and global GM volume found no significant associations. e23 Longitudinally, neither baseline nor on-study changes in WM lesion measures predicted changes in GM volume over the 4-year follow-up. e24

CGM in SPMS
The observed relationship between cortical volume or thickness and global WM lesion load in patients with SPMS was not consistent in the 4 available studies. Two studies found significant associations with lower cortical volume (p < 0.001 and <0.05). e16,e40 Furthermore, cortical thickness was evaluated in another 2 studies based on 1 and the same study population; neither study found any significant association between T2 LV and global mean cortical thickness. e17,e34 One of 4 cross-sectional studies assessing regional WM lesions observed relatively strong correlations between lower cortical volume and T2 LV in the same or adjacent lobes (r values ranging from −0.67 to −0.79, p < 0.001). e40 In the 3 remaining studies, the associations with lower cortical volume or thickness were weak e45,e46 or nonsignificant. e23 The only longitudinal study available investigated atrophied T2 LV (T2-weighted lesional tissue subsequently substituted by CSF) in patients with SPMS and primary progressive MS (PPMS) in a combined progressive MS group, finding no associations with baseline cortical volume or volume change (follow-up time 5.5 years). e10

DGM in SPMS
In the 6 cross-sectional publications that considered global WM lesions, results were somewhat conflicting. Two studies found no associations with lower DGM volume e16,e55 ; in the other 4 studies, however, T1 e53 or T2 e17 LV was associated significantly with both total DGM volume (p values ranging from <0.01-0.04) and separate DGM structures such as the hippocampus, e52 thalamus, and caudate nucleus e40 (r values ranging from −0.69 to −0.88, p < 0.001-0.018). Two of 4 studies e23,e40,e45,e46 that included results for regional WM LV or distribution showed significant associations e40,e46 (p values ranging from <0.001-<0.05).
The sole longitudinal study found no association between atrophied T2 LV (described in the previous section) and baseline thalamic volume or volume change. e10

Primary Progressive MS
The relationship between WM lesions and GM measures in patients with PPMS was assessed in 11 cross-sectional studies and longitudinally in 2 studies.
Three studies performed analyses involving global GM volume, while CGM and DGM measures were each considered in 9 studies. Three studies considered regional WM LV or distribution.
Included studies are described in eTables 1 and 2, links.lww. com/WNL/B816, and a more detailed version of the respective sections is given in eAppendix 2. Figure 3 illustrates the main results from this section.

Global GM in PPMS
The cross-sectional associations between global WM lesion measures and global GM volume in patients with PPMS were variable. One study reported a significant correlation with T2 LV (r = −0.68, p < 0.001), e17 while the other found no significant associations with either T2, T1, or gadoliniumenhancing LV or lesion numbers. e59 In the available longitudinal study, baseline WM lesion measures were not related to GM volume change over 12 months. e60

CGM in PPMS
Cross-sectional results for global WM lesion measures and CGM volume or thickness in patients with PPMS were divided. Three studies found associations between T1 e61 and T2 e34,e40 LV and total (r = −0.508, p < 0.05) e61 and regional (r values ranging from −0.605 to −0.85, p values ranging from <0.001-<0.01) e40 cortical volume and total cortical thickness (p < 0.05). e34 In the other 3 studies, no significant associations were found for either cortical volume e31,e62 or thickness. e17 Of 3 publications assessing regional WM lesion measures, 1 study found a relationship with cortical volume in anatomically connected areas (p < 0.001), e40 while in the other 2, the associations with cortical thickness or volume were weak e46 or absent. e45 Only 1 longitudinal study was identified, finding no associations between atrophied T2 LV (described in previous section) and baseline cortical volume or volume change. e10 Of 3 cross-sectional publications assessing regional WM lesions, e40,e45,e46 lower regional DGM volume was related to regional T2 LV in 2 studies (p values ranging from <0.001-<0.05). e40,e46

DGM in PPMS
Again, only 1 longitudinal study was available, and for both baseline thalamic volume and volume change, no relationship to atrophied T2 LV (described in the previous section) was found. e10

Results for Mixed MS Groups
A number of studies e1,e9,e10,e16,e17,e23,e34,e46,e53,e55,e64-e90 reported analyses relating GM atrophy measures to WM lesion measures in heterogeneous groups of patients with MS encompassing different disease phenotypes. Full results of these studies are reported in eAppendix 2, links.lww.com/ WNL/B816. Briefly, in most cross-sectional studies, GM atrophy and WM lesions were significantly associated; in longitudinal studies, results were more variable.

Comparisons Between Disease Phenotypes
Some of the studies discussed in the previous sections included multiple disease phenotypes in a single study. Such a design eliminates differences between image acquisition and image analysis approaches that may otherwise account for differences between disease phenotypes observed from separate studies and therefore can shed the most direct light on whether the relationship between GM atrophy and WM lesions might differ between disease types. Table 2 summarizes the observed associations in articles including multiple phenotypes, and full reports of the studies are given in eAppendix 2, links.lww.com/WNL/B816. We focus on whether the observations differed between disease types and, when available, on the direct statistical comparisons between disease types. In summary, for global GM, CGM, and DGM, both crosssectional and longitudinal studies found the most consistent associations with WM lesions in RRMS, while the associations for CIS, SPMS, and PPMS were more variable ( Table 2). In 11 of 15 studies, the largest patient group consisted of patients Continued with RRMS, often in a great majority. Such imbalance may cause the studies to detect significant associations only in the larger patient group, merely because of power and not due to a lack of true association in the smaller (progressive) patient group.

Discussion
This systematic review assessed the existing evidence regarding an association between brain WM lesions and GM atrophy in MS. Surveying results from cross-sectional and longitudinal studies of different phenotypes and with varying anatomic regions of interest has resulted in a comprehensive picture. More WM lesions were associated with more GM atrophy (Table 3), especially in RRMS and less consistently so in progressive MS.
The quality of evidence was mostly rated as fair, with no correction for potential confounders (e.g., therapeutic and physiologic factors), short follow-up time, and small or unbalanced disease groups (as highlighted in the previous section) as the main risks of bias.
The clear trend emerging from cross-sectional and longitudinal studies for both global and regional associations was that more WM lesions were related to more or faster GM atrophy. Patients with high WM lesion burden may be expected to also have extensive damage to other brain structures, not necessarily because one causes the other but possibly also because an advanced disease stage acts as a common denominator. To further investigate, each disease type was evaluated and compared; the association was observed frequently in all disease types, most consistently in RRMS. However, the relationship was more variable for longitudinal than for crosssectional outcomes.
In mixed MS groups, the lack of significant associations in longitudinal studies could be related to group heterogeneity. Furthermore, variable treatment regimens across patients affect the interpretation of all studies, especially more recent longitudinal studies. Here, the time that patients have spent under potent treatment is often considerable and may modulate not only the observed association between WM lesions and GM atrophy but also the main pathologic substrate of the neurodegenerative process.
Current knowledge from neuroimaging and histopathology implies that GM neurodegeneration is driven both by events secondary to WM inflammation and by primary disease mechanisms within the GM. Adding to the complexity, these mechanisms seem to act simultaneously, with additive effects. 21 Strong and consistent associations with WM lesions were found in all GM regions in RRMS and in DGM in CIS; this suggests that early GM neurodegeneration is mainly secondary to damage in the WM: after chronic inflammation in WM, neuronal injury and damage to mitochondria with resulting energy deficiency initiate several neurodegenerative cascades. The degenerative process can move forward toward the axonal terminal (anterograde or wallerian degeneration) or backward toward the cell soma (retrograde degeneration), leading to neuronal loss and atrophy in connected GM regions. 22 In both CIS and RRMS, the most consistent relations were seen in DGM and the thalamus.
Connecting and relaying information between subcortical areas and the neocortex through different WM tracts, 23 it seems plausible that thalamic GM components are vulnerable to damage through retrograde degeneration. 24 In progressive MS phenotypes, while GM atrophy was more widespread, affecting most DGM structures e40,e46,e55 and Abbreviations: CIS = clinically isolated syndrome; GM = gray matter; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis. Presence or absence of the association between white matter lesion measures and GM atrophy measures is indicated as ✓ (association present), χ (association not present), or ✓/χ (association present for some analyses, not present for other analyses). If the disease phenotype was not investigated in the study, this is indicated as -.
cortical areas, e40,e46 the relationship with focal WM lesions was more varied although still present in the majority of studies. e17,e34,e46,e55 These results, interpreted together with neuropathologic studies showing continued, widespread GM atrophy development, at least partly independently of focal inflammatory WM lesions, [25][26][27] suggest that in progressive MS the neurodegenerative disease mechanism may be a mainly primary process. Alternatively, in long-standing MS with many tracts affected, the relationships between primary lesional damage and downstream GM atrophy may become too complex and too variable across individuals to disentangle. Furthermore, GM lesions, often found more prominently in progressive MS, may also propagate GM atrophy and contribute to its less consistent association with WM lesions. e53 In addition, consistent GM atrophy patterns found in patients with CIS e70 suggest that some primary degenerative processes may be present throughout the disease.
The reviewed literature suggests that the mechanisms of neurodegeneration in MS are not static through the disease course, so the therapeutic targets, interventions, and subsequent monitoring will most likely differ for the various patient groups. To obtain fully individualized and optimized patient treatment, we have summarized important research aims and suggestions for future research in Table 4.
Our study has several limitations. Diagnostic criteria and hence the separation between CIS and MS varied over time. The effect of physiologic variability and therapeutic interventions was not consistently accounted for in the reviewed articles. Whether treatment was used and what type were mostly stated but rarely adjusted for in the analyses. Therefore, effects of individual treatments on WM lesions or (primary or secondary) GM atrophy, which potentially change the observed relationship between the 2 processes for each patient, could cloud our interpretation of the disease mechanisms.
In longitudinal studies, the group sizes were often smaller, and the majority followed up the patients for ≤2 years. Such short follow-up durations most likely affected the ability to detect temporal associations, considering that neurodegeneration is a slowly progressive process. e24 Moreover, brain atrophy is cumulative and may exhibit a ceiling effect and delayed effects from previous exposures or previous pathologic damage. 28 Technical factors are well known to affect brain measurements 28 : intrastudy and interstudy variability in MRI scanners and acquisitions (e.g., field strength, slice thickness, 2-/3dimensional acquisitions, pulse sequence type and parameters), image (pre)processing tools, and analysis software. This makes the interpretation and comparison of results challenging. The 20-year time frame of included articles, during which MRI

Research aims Suggestions
Understand the details of the spatiotemporal relationship between white matter lesions and gray matter atrophy in multiple sclerosis.
Imaging studies, preferably of longitudinal design, focusing on pathology in defined structurally or functionally connected regions. Minimize technical interstudy and intrastudy variability in imaging studies and include acquisitions needed to detect and study relevant pathology (e.g., gray matter lesions).
Combining or interpreting results of imaging studies in context with knowledge obtained through histopathologic or molecular studies. Investigate each neurodegenerative process separately for each disease phenotype, defined not only by clinical characteristics but also by biological and imaging markers to better capture the dominant pathologic substrate. 30 Consider the type and duration of therapeutic interventions that included participants have received. Specify the neurodegenerative pathway targeted in clinical trials; interpret results separately for each disease phenotype; and compare them directly.
Untangle the neurodegenerative processes secondary to focal inflammatory damage from those primarily arising in the gray matter.
Determine which neurodegenerative process is the dominant driver of gray matter atrophy in different stages of the disease.
Develop therapeutic interventions targeting specific neurodegenerative processes. In cross-sectional studies in particular, WM lesion volumes were related mostly to global, cortical, and deep GM volumes, and those significant associations were almost without exception negative, indicating that higher WM lesion volumes were associated with lower GM volumes or lower cortical thicknesses.

No. 2: WM lesions are most clearly linked to GM atrophy in RRMS
The most consistent relationship between WM lesions and GM atrophy was seen in patients with RRMS. In this relapsing phenotype, significant associations were found in the majority of studies considering global, cortical, and deep GM. A relationship with deep GM and especially thalamus volumes was particularly consistent in RRMS and in CIS.
No. 3: In progressive disease WM lesions are mostly, but less consistently, linked to GM atrophy Studies of the progressive disease types showed more variable associations: for both SPMS and PPMS, WM lesion measures were related to global GM volume in the majority of studies, but for cortical and deep GM, associations were less consistent.
technology has achieved major leaps of improvement, means that earlier studies have to be evaluated in the light of the concurrently available technology and knowledge. Furthermore, the large variability in image acquisition, analysis methods, and outcome measures, combined with uncertainties about potential confounders such as treatment, made it impossible to conduct a meaningful and interpretable metaanalysis of the results reported in the reviewed articles.
Statistical issues may also have influenced results. Sample sizes were often unbalanced between disease types, especially with small progressive groups being compared to larger relapsingremitting groups. Furthermore, the majority of studies focused on patients with RRMS, which limits our ability to draw conclusions for progressive disease types.
To elucidate the pathophysiologic relationship between inflammatory WM lesions and neurodegenerative changes in GM, this review has an obvious limitation in that statistical associations do not prove causation. However, the many imaging studies included provide the possibility to investigate these relations in vivo in a large number of patients in different disease stages. Although in this study a spatiotemporal relationship between changes in GM structures and WM lesions was found, we cannot draw any conclusions about whether this process starts with demyelination in WM or whether the primary defect is in the axon or neuron itself, with demyelination as a secondary effect. 29 To widen this question of causality, some researchers suggest that the association seen between WM lesions and lower GM volume in certain regions is not causally linked through axonal degradation but is mainly due to a common close proximity to inflammatory soluble factors in the CSF. e9 Due to capacity and limiting the scope of this systematic review, we included only MRI measures obtained by conventional MRI sequences. Advanced imaging methods would be interesting to review, which by necessity would require more attention to the myriad technical differences between such studies.
We found that the majority of the literature overwhelmingly reported an association between WM lesions and global or regional GM atrophy. The association was most consistent in RRMS but more variable in progressive phenotypes and CIS. This suggests that GM neurodegeneration is mostly secondary to damage in the WM during early disease stages, while more detached and dominated by other, possibly primary neurodegenerative disease mechanisms in progressive MS.
These findings are of great importance for patient treatment and research, indicating that the most effective targets for neuroprotective treatment change throughout the disease course.
To further disentangle the secondary GM atrophy caused by WM damage from primary neurodegenerative disease mechanisms, more studies investigating the spatiotemporal relationship between the 2 pathologic phenomena are needed, preferably with extensive follow-up time and a direct comparison with the different disease phenotypes.